Many of the chemical reaction and separation processes used in the pharmaceutical and fine chemicals industry require the use of organic solvents. These solvents are often volatile and sufficiently water-soluble to contaminate air emissions and aqueous discharge streams, adding to the environmental burden and the cost of downstream processing and recovery operations. Recognized hazardous industrial solvents include chlorinated hydrocarbons, such as methylene chloride, chloroform and carbon tetrachloride; aromatic hydrocarbons, such as benzene, toluene and xylene; ketones, such as acetone, methylethylketone (MEK) and methylisobutylketone (NUBK); and ethers, such as tetrahydrofuran (THF) and diethyl ether.
The use of tetrahydrofuran (THF) in pharmaceutical processing is problematic as the solvent is used for a range of reactions which must be carried out under anhydrous conditions, such as Grignard reactions. The desired product is often obtained by aqueous precipitation. Since THF is soluble in the water phase, it typically is recovered by distillation which leads to problems not only with the recovery of solvent, but also with the loss of anti-oxidants, such as BHT, which are added to arrest the potentially dangerous formation of peroxides. The volatility of the solvent can also lead to unwanted vapor emissions to the environment. In a typical reaction sequence using THF as the solvent, a reaction mixture is extracted with water to remove salts and polar substituents. This may cause some of the solvent to be dragged into the aqueous phase while the rest remains in the product phase. The solvent must then be recovered from the aqueous phase for recycling and to minimize loss to the environment. The product must then be isolated, which may involve a switch to a solvent in which the product will crystallize. Continuous switching of solvents is problematic in chemical synthesis because it is time-consuming, generates mixed solvent systems which must be separated, introduces potential pollutants which must be removed and produces large volumes of waste.
Another often used, but environmentally harmful, solvent is methylene chloride. Methylene chloride is used both as a reaction medium and for extractive separation processes. Equipment cleaning using solvents can also contribute to the environmental pollution problem.
In recent years, federal and state regulations have been passed which strongly discourage the use of solvents which are not environmentally benign. Of particularly strong impact is the Pollution Prevention Act passed by Congress in October 1990 and the Resource Conservation and Recovery Act of 1988. These laws strongly encourage hazardous waste minimization by recovery and recycling of organic solvents. Such a strategy is less expensive than collection, treating or disposal of hazardous wastes, and is also of much less risk to workers, the environment and the community. In addition, substitution of non-volatile organic compounds for the commonly used volatile solvents is strongly encouraged.
Owing to these laws and increased public awareness of the harm done by such solvents, there is considerable interest in ameliorating the deleterious environmental effects associated with solvent usage in pharmaceutical reaction processes. The different approaches that are being considered include (i) a search for new synthetic procedures that utilize less hazardous solvents, (ii) the establishment and exploitation of extensive computer data bases on solvents, (iii) the use of solvent mixtures to obtain the desired solvation properties, and (iv) the intelligent design of reaction/separation trains to minimize mixing of solvents in different operations, and thereby minimize the problems associated with their recovery and recycle. However, the development of new synthetic procedures may be at the expense of yield and productivity, and the time-frame for such developments is probably fairly long. Also, process modifications involving material substitution require complete approval (and in many cases preapproval if a drug is concerned) by the FDA before the new product can be marketed. This can be an expensive and time-consuming process, and may result in a temporary shutdown of production while necessary changes are being implemented.
It is therefore desirable to provide a solution to the problem which can be implemented in the short or intermediate term and which involves minimal alteration or disturbance to the current pharmaceutical processes. Use of environmentally more benign replacement solvents, combined with simplified recovery and recycling processes, is therefore particularly appealing. Current solvent recovery and recycling processes focus on distillation and various chromatography steps. Estimated savings due to recycling are in most cases offset by the cost of the recovery process equipment, still bottoms disposal and makeup for non-recovered solvent. It is thus desirable when selecting suitable replacement solvents that difficult separation problems be avoided, that more efficient recovery of solvents be facilitated, and appropriate solvation properties be attained while ensuring that the potential for environmental contaminations is minimized.
A synthetic route to n-alkyl tetrahydrofurfuryl ethers has been previously described. Kirner et al. JACS 1930 (52):3251-3256 (1930). While the synthesis may be modified for the preparation of n-alkyl tetrahydro-3-furan ethers, no report of these compounds in the literature has been found. Various uses of alkyl tetrahydrofurfuryl ethers have been reported, including absorption refrigeration crease-proofing of cellulosic fabrics, in detergent compositions and as modifiers in the polymerization reactions of conjugated dienes. However, there has been no report on their use as a replacement solvent for THF in chemical and pharmaceutical reactions.